The compounds of the present invention belong to the class of the diterpenoid derivatives and have demonstrated to possess cardiovascular properties which render them useful for the prevention and/or treatment of hypertension, heart failure, cardiac hypertrophy, renal failure, glomerulosclerosis, proteinuria, vascular stenosis after vascular surgery and to prevent organ damage in hypertensive patients.
Cardiovascular diseases are still the first cause of morbidity and mortality in the western world; among these, hypertension and heart failure are two frequent diseases. Hypertension is one of the most important cardiovascular risk factor and more than one third of the population over 60 suffers from this disease. Congestive heart failure affects 1-2% of the population and even 10% of the very elderly; the percentage is expected to rise (Sharpe N., et al., The Lancet, 1998, 352, (suppl. 1), 3-17). Beside, hypertension may be one of the most important causes of heart failure in the elderly (Remme W. J., et al., Eur. Heart J., 2001, 22, 1527-1560). Although a number of effective drugs are available for the treatment of both hypertension and heart failure, further research is in progress to find more effective and safer compounds. Several drugs are used in combination for the treatment of heart failure, and among positive inotropic agents, digoxin is the most prescribed digitalis cardiac glycoside that can improve the myocardial performance. However, a very well known drawback of digitalis drugs is their arrhythmogenic side effect. Evidence of digitalis toxicity such as disturbances of conduction and cardiac arrhythmias which are characteristics of digitalis toxicity (Hoffman, B. F., et al., Digitalis and Allied Cardiac Glycosides; The Pharmacological Basis of Therapeutics, 8th ed.; Goodman Gilman A.; Nies A. S., Rall T. W., Taylor P., Eds.; Pergamon Press, New York, 1990, 814-839) emerges at two- to three-fold higher serum concentration than the therapeutic dose.
The present compounds are useful for the prevention and/or treatment of cardiovascular disorders. Indeed, said compounds are able to antagonize the effects of mutant α-adducin and ouabain which are both known to be implicated in human hypertension and related organ complications and cardiac hypertrophy and/or failure.
Furthermore, the instant compounds do not inhibit the Na-K ATPase pump and therefore do not present the safety issue (e.g., arrhythmogenic side-effects) associated to such inhibition.
Endogenous ouabain (EO) has been widely recognized as a new hormone able to control blood pressure through different mechanisms and in particular through the modulation of the renal Na handling. Moreover, high circulating levels of EO have been found to be associated with cardiac and renal hypertrophy in animal models such as the Ouabain Hypertensive Rats model (OHR) (Ferrandi M., et al., J. Biol. Chem., 2004, 279, 32, 33306) and with cardiac and renal dysfunctions in humans (Pierdomenico S. D., et al., Am. J. Hypertens., 2001, 14, 1, 44; Stella P., et al., J. Int. Med., 2008, 263, 274).
Mutations in the genes coding for the cytoskeletal protein adducin were found to be associated to hypertension and related organ complications (Bianchi G., et al., Hypertension, 2005, 45, 3, 331). In particular, adducin is involved in many cellular processes, some of which being affected by the mutations and having relevance in hypertension and related organ complications such as:
i. the regulation of the residential time of some integral proteins on the cell surface (Na-KATPase, integrin) (Efendiev R., et al., Circ. Res., 2004, 95, 11, 1100; Torielli L., et al., Am. J. Renal Physiol., 2008, 295, 2, F478);
ii. the influence on the constitutive Na+ reabsorption capacity of the renal tubular cell (Bianchi G., et al., Hypertension, 2005, 45, 3, 331);
iii. the regulation of the expression of some glomerular podocyte proteins (nephron, synaptopodin) associated to proteinuria and progression of renal damage both in animal models and humans (Ferrandi M., et al., J. Mol. Med., 2010, 88, 203).
Experimental evidence obtained both in the Milan hypertensive rat model (MHS) and in humans supports the role of adducin polymorphisms in hypertension and related organ complication, including deterioration of the renal function and proteinuria (Citterio L., et al., Biochim. Biophys. Acta, 2010, Apr. 8).
Both EO and mutant adducin can lead to hypertension, organ hypertrophy, renal failure, proteinuria, negative vascular remodeling and increased cardiovascular risk through the up-regulation of the Na-K pump, activation of the Src-dependent signal transduction pathway or other pathways modulating actin cytoskeleton.
The abietic acid and dehydroabietic acid derivatives object of the present invention have been found to be endowed of suitable cardiovascular pharmacological properties, and/or able to prevent organ damage, and/or prevent proteinuria. In particular, the abietic acid or dehydroabietic acid derivatives object of the present invention have been found to antagonize the effects of EO and mutant adducin on blood pressure and renal function deterioration and proteinuria.
A further important biological activity of the present compounds resides in their ability to reduce proteinuria induced by endogenous ouabain and to prevent organ damage.
Some dehydroabietic acid derivatives have been described as being endowed of anti-ulcer properties (Wada H., et al., Chem. Pharm. Bull., 1985, 33, 4).
WO2005084141 disclosed the specific dehydroabietane derivative 1 as being endowed of said properties through acyl-CoA:cholesterol acyltransferase inhibition properties.

EP1421936 (i.e., the European national phase, now refused, of WO2002087559) disclosed potassium channel opener derivatives of formula 2. However, only three derivatives structurally different to the compounds of the preterit invention were specifically reported among. The inventors of this patent application also published further data regarding said compounds of formula 2 acknowledging the fact that abietic derivatives were not active on large-conductance K− despite only very small differences in their chemical structures channels contrarily to the pimaric acid derivatives disclosed.

WO10024298 disclosed potassium channel modulator derivatives of formula 3 which are structurally different to the compounds of the present invention.

The preparation of very few antiarrhythmic compounds derived from esterification of abietic acid have also been reported some forty years ago (Sefcovic P., et al., Chemicke Zvesti, 1961, 15, 554); however, the compounds of the present invention were not disclosed nor suggested.
An enantioselective and catalytic synthesis of an oxime abietic derivative has been disclosed starting from the corresponding enantic pure nitro analogue (Czekelius C., et al., Angew. Chem. Int. Ed., 2005, 44, 612).
More than forty years ago, synthesis of dehydroabietic derivatives had been described, the latter being motivated for the known antibacterial properties of those scaffold-containing adducts (von Rudolf A., et al., Liebigs Ann. Chem., 1969, 725, 154).
Nevertheless, as the literature demonstrates, the need of new derivatives endowed with suitable cardiovascular pharmacological properties, and/or able to prevent organ damage, and/or prevent proteinuria still persists.